Diabetes mellitus (DM) is one of the most common chronic diseases in the United States and is becoming more common as the population ages. Among the chronic complications of DM, polyneuropathy is the most prevalent. It seems likely that progress in the understanding of any of the chronic complications would be likely to have significance in terms of the understanding of the causes and ultimate cure of other chronic complications. An accurate understanding of the pathology of any disease in humans is a prerequisite to the identification of animal models and other approaches to understanding the cause, development and cure for the diseases. Pathology of DM neuropathy has not been characterized. Pathological studies utilizing critical morphometric techniques have resulted in contradictory conclusions and have not been adequate since they have concerned studies of small nerve biopsies. Recent studies, in our laboratory, of nerves from the legs of patients with DM polyneuropathy, obtained at autopsy, have shown that there is a proximo-distal graded loss of myelinated fibers. The degree of loss is significantly correlated with the frequency of focal fascicular lesions (FFL). These FFL on pathological grounds are likely due to ischemia, a conclusion supported by subsequent studies in this laboratory showing similar FFL in nerve biopsies with vasculitis. Considering the well known relationship of DM microvascular disease to the other chronic complications of diabetes this finding in DM neuropathy is perhaps not unexpected. Our plan is to collect a large sample of nerves from DM with various stages of neuropathy and a control group of nerves from autopsies of nondiabetics controlled for age, sex, and whenever possible, clinical neuropathy. These nerves will be subjected to systematic morphometric analysis in order to identify the three dimensional morphometry of FFL, the relationship and character of regional abnormalities in the vasa nervorum to these FFL, and the extent to which these FFL account for the neuropathy. These various parameters will be correlated with various clinical and autopsy parameters. The overriding goal is to identify the nature of the vascular abnormality of the vasa nervorum which produces FFL. The next step will be to determine the pathogenesis of the microvascular lesion which will direct studies into its prevention and/or cure.